EP3562489A1 - Intraocular drug delivery device and associated methods - Google Patents
Intraocular drug delivery device and associated methodsInfo
- Publication number
- EP3562489A1 EP3562489A1 EP17885743.9A EP17885743A EP3562489A1 EP 3562489 A1 EP3562489 A1 EP 3562489A1 EP 17885743 A EP17885743 A EP 17885743A EP 3562489 A1 EP3562489 A1 EP 3562489A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- active agent
- eye
- biodegradable
- acid
- matrix
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
- A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K9/0012—Galenical forms characterised by the site of application
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- A61K9/0051—Ocular inserts, ocular implants
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
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- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
- A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
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- A61L2400/00—Materials characterised by their function or physical properties
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- A61L2430/00—Materials or treatment for tissue regeneration
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Definitions
- the present invention relates to systems, methods, and devices for the sustained and targeted (local) delivery of a pharmaceutical active agent into a subject's eye. Accordingly, the present invention involves the fields of polymer chemistry, material science, polymer science, drug delivery, formulation science, pharmaceutical sciences, and medicine, particularly ophthalmology.
- Age-related macular degeneration (AMD) and glaucoma are two of the leading causes of blindness in the United States and across the world.
- Present glaucoma therapies generally require polypharmacy, where subjects are often prescribed several topical agents that must be applied to the eye with varying frequencies, in some cases up to 3 or 4 times a day. These dosing regimens are often difficult for subjects to consistently follow, and many individuals progress to needing surgical treatments such as intraocular shunts or trabeculectomies, which have significant attendant complications.
- Postoperative surgery inflammation is associated with raise intraocular pressure (IOP), and increase the likelihood of cystoid macular edema (CME), synechial formation, posterior capsule opacification (PCO), and secondary glaucoma.
- IOP intraocular pressure
- CME cystoid macular edema
- PCO posterior capsule opacification
- Secondary glaucoma Patient compliance is of concern in the management of postoperative inflammation because multiple eye drops must be taken multiple times per day at regular intervals over the course of weeks. Poor compliance compromises the efficacy of topical drugs, which are further limited by corneal absorption and have highly variable intraocular concentrations during the therapeutic course.
- Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye.
- Uveitis is estimated to be responsible for approximately 10% of the blindness in the United States.
- Postoperative cataract surgery inflammation can be well controlled by improving patient compliance.
- Available literature and experience shows penetration of the drug after topical administration is poor and higher systemic concentration means frequent systemic adverse events. All of these factors highlight the need for sustained intraocular delivery for pharmaceutical active agents to effectively control inflammation.
- a method of delivering an active agent to a posterior segment of an eye of a subject can include placing a biodegradable active agent matrix within a lens capsule of the subject to deliver the active agent to a posterior segment of the eye.
- the biodegradable active agent matrix comprises an active agent present in an amount to deliver a therapeutically effective dose of the active agent to the posterior segment of the eye from the lens capsule.
- FIG. 1 is a photograph showing a bioerodible dexamethasone implant (BDI), in accordance with some examples of the present disclosure.
- BDI bioerodible dexamethasone implant
- FIG. 2 is a bar graph showing the amount of an active agent present in various eye tissues following implantation of an intraocular device in accordance with a further aspect of the present invention.
- FIG. 4 time vs concentration profile of an example BDI implant with 120 to 160 ⁇ g of dexamethasone (DXM) in aqueous and vitreous humor of New Zealand White (NZW) rabbits.
- DXM dexamethasone
- FIG. 5 time vs concentration profile of an example BDI implant with 120 to 160 ⁇ g of DXM in iris/ciliary body and retina/choroid of NZW rabbits.
- FIG. 6 is a graph of time vs. concentration profile of an example BDI implant and topical drops in aqueous humor of New Zealand white rabbits.
- FIG. 7 is a graph of time vs. concentration profile of an example BDI implant and topical drops in vitreous humor of New Zealand white rabbits.
- FIG. 8 is a graph of time vs. concentration profile of an example BDI implant and topical drops in retina/choroid of New Zealand white rabbits.
- FIG. 9 is a graph of time vs. concentration profile of an example BDI implant and topical drops in iris/ciliary body of New Zealand white rabbits.
- FIG. 10 is a graph illustrating the effect of croscarmellose concentration on drug release for some example BDI implants.
- FIG. 13 is a graph of time vs. concentration profile of an example BDI implant and topical drops in aqueous humor of New Zealand white rabbits.
- FIG. 14 is a graph of time vs. concentration profile of an example BDI implant and topical drops in vitreous humor of New Zealand white rabbits.
- FIG. 15 is a graph of time vs. concentration profile of an example BDI implant and topical drops in retina/choroid of New Zealand white rabbits.
- FIG. 16 is a graph of time vs. concentration profile of an example BDI implant and topical drops in iris/ciliary body of New Zealand white rabbits.
- FIG. 17 is a graph of retinal thickness vs. time profile of an example BDI implant and topical drops as compared to normal control.
- FIG. 18 is a graph of time vs. concentration profile of an example BDI implant and topical drops in aqueous humor of New Zealand white rabbits.
- FIG. 19 is a graph of time vs. concentration profile of an example BDI implant and topical drops in vitreous humor of New Zealand white rabbits.
- FIG. 20 is a graph of time vs. concentration profile of an example BDI implant and topical drops in retina/choroid of New Zealand white rabbits.
- FIG. 21 is a graph of time vs. concentration profile of an example BDI implant and topical drops in iris/ciliary body of New Zealand white rabbits.
- FIG. 22 is a graph of retinal thickness vs. time profile of an example BDI implant and topical drops as compared to normal control.
- active agent biologically active agent
- pharmaceutically active agent pharmaceutically active agent
- drug drug
- compositions may be used interchangeably herein, and refer to a combination of two or more elements, or substances.
- a composition can include an active agent, an excipient, or a carrier to enhance delivery, depot formation, etc.
- effective amount refers to an amount of an ingredient which, when included in a composition, is sufficient to achieve an intended compositional or physiological effect.
- a “therapeutically effective amount” refers to a substantially non-toxic, but sufficient amount of an active agent, to achieve therapeutic results in treating or preventing a condition for which the active agent is known to be effective. It is understood that various biological factors may affect the ability of a substance to perform its intended task.
- an "effective amount” or a “therapeutically effective amount” may be dependent in some instances on such biological factors. Further, while the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a subjective decision. However, the determination of an effective amount is well within the ordinary skill in the art of pharmaceutical and nutritional sciences as well as medicine.
- subject refers to a mammal that may benefit from the administration of a composition or method as recited herein.
- subjects include humans, and can also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, aquatic mammals, etc.
- intraocular lens refers to a lens that is utilized to replace a lens in the eye of a subject. Such intraocular lenses can be synthetic or biological in nature. Furthermore, in some aspects the term “intraocular lens” can also refer to the original natural lens that is associated with the eye.
- ciliary sulcus refers to the space between the posterior root of the iris and the ciliary body of the eye.
- the term “substantially” refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
- an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
- the exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained.
- the use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of an action, characteristic, property, state, structure, item, or result.
- compositions that is "substantially free of particles would either completely lack particles, or so nearly completely lack particles that the relevant effect would be the same as if it completely lacked particles.
- a composition that is "substantially free of an ingredient or element may still actually contain such item as long as there is no measurable effect thereof.
- the term "about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint.
- the term "at least one of is intended to be synonymous with “one or more of. " For example, “at least one of A, B and C” explicitly includes only A, only B, only C, and combinations of each.
- An intraocular drug delivery device can provide improved ophthalmic drug delivery by alleviating the need for multiple injections or complex eyedrop regimens by providing an intra-capsular reservoir which is implantable and biodegrades such that subsequent surgery is often unnecessary. Further, the device can deliver a variety or combination of different medicines.
- a novel intraocular drug delivery device, system, and associated methods for providing sustained release of ocular active agents for extended periods of time are disclosed and described.
- One problem with many eye diseases such as Age-related Macular
- ATD Alzheimer's disease
- neovascularization is a key pathobiological process in a variety of eye diseases, such as AMD, proliferative diabetic retinopathy, vascular occlusive disease, and radiation retinopathy. Additionally, the incidence of glaucoma is increasing worldwide. Many other disorders, including severe uveitis and geographic atrophy in AMD, can be treated using such an intraocular drug delivery device. Thus, an implantable, generally sutureless drug delivery device for placement in the anterior segment of the eye has great potential to improve the quality of life for subjects.
- the drug delivery device can continuously deliver dexamethasone or other antiinflammatory or therapeutic agents with near zero order kinetics for two weeks or more. Treatment of uveitis needs long term (6-8 weeks) sustained delivery of anti-inflammatory agents. The biggest disadvantage with topical drops is that negligible concentrations of drugs will reach the posterior segment of the eye and especially the retina/choroid.
- the designed and disclosed drug delivery device can deliver dexamethasone and/or other therapeutic agents continuously with near zero order kinetics both to the anterior and posterior segments of the eye, thus effectively controlling the inflammation.
- the present invention provides systems, devices, and associated methods for the delivery of active agents into the eye of a subject.
- the systems, devices, and associated methods can be positioned within the anterior segment of the eye (e.g. within the lens capsule) of a subject to deliver an active agent to the posterior segment of an eye of the subject.
- Non-limiting examples of ocular regions found within the posterior segment of the eye can include at least one of the vitreous humor, the choroid, and the retina.
- the active agent can also be delivered to the anterior segment of the eye.
- the anterior segment of the eye can include at least one of the aqueous humor, the iris, and the lens capsule.
- the intraocular device can be sutureless.
- a sutureless device can be defined as a device or structure that can be inserted and retained within a lens capsule without the need for a suture to hold the device in place.
- the device can be implantable within the lens capsule during cataract surgery, essentially "piggybacking" on the cataract extraction, and thus eliminating the need for additional surgical procedures.
- One benefit to "piggybacking" on the cataract extraction is the ability to deliver steroids, antibiotics, and/or various nonsteroidal agents directly to the eye after surgery, thus helping to minimize complications such as cystoid macular edema.
- the device can be implanted in a surgery that is separate from a cataract procedure, e.g., subsequent to a previous cataract extraction with reopening of the lens capsule.
- the device can be implanted post-cataract surgery for treatment of macular degeneration, retinal vein or artery occlusion, diabetic retinopathy, macular edema (e.g. from diabetes, uveitis, intraocular surgery, etc.), retinal degenerations where a neuroprotectant delivery is indicated, or the like.
- macular degeneration e.g. from diabetes, uveitis, intraocular surgery, etc.
- macular edema e.g. from diabetes, uveitis, intraocular surgery, etc.
- retinal degenerations where a neuroprotectant delivery is indicated, or the like.
- the device can be provided in the form of an implant containing an active agent within a biodegradable or bioerodible polymer matrix.
- the biodegradable active agent matrix can include an active agent in an amount to deliver a therapeutically effective amount or therapeutically effective dose of the active agent to the posterior segment of the eye from the lens capsule.
- a therapeutically effective amount or therapeutically effective dose can vary depending on the particular therapeutic agent being employed in the biodegradable active agent matrix. Further, the therapeutically effective amount or therapeutically effective dose can vary depending on the severity of the condition being treated. Nonetheless, the active agent can be present in an amount to facilitate delivery of the active agent from the anterior segment of the eye (e.g. from the lens capsule) to the posterior segment of the eye.
- the therapeutically effective amount or therapeutically effective dose can typically range from about 50 micrograms (meg) to about 10 milligrams (mg), depending on the active agent being employed and the severity of the condition. In some specific examples, the therapeutically effective amount or therapeutically effective dose can range from about 50 meg to about 600 meg. In yet other examples, the therapeutically effective amount or therapeutically effective dose can range from about 100 meg to about 400 meg, from about 100 meg to about 300 meg, or from about 200 meg to about 400 meg.
- the active agent can typically be present in the implant at a concentration of from about 5 wt% to about 25 wt%, or from about 5 wt% to about 15 wt%, or from about 10 wt% to about 20 wt%. Further still, depending on the dosage requirements, one, two or more implants can be implanted per eye to achieve a therapeutically effective dose.
- the biodegradable active agent matrix can be configured to bioerode to provide controlled release of the therapeutically effective amount over a period of days, weeks, or months.
- the therapeutically effective amount can be released over a period ranging from about 1 week to about 10 weeks.
- the therapeutically effective amount can be released over a period ranging from about 1 week to about 3 weeks, from about 2 weeks to about 6 weeks, or from about 5 weeks to about 8 weeks.
- the period can often range from 2 months to 12 months, and in some cases from 2.5 months to 5 months.
- bioerodible lipid polymers and/or bioerodible polycaprolactone can be used as an extended release matrix material.
- the intracapsular positioning of the device within the lens capsule can affect delivery of the active agent to the posterior segment of the eye.
- positioning of the implant at a location inferior and peripheral to the intraocular lens (IOL) or within the inferior peripheral capsule can provide suitable delivery of the active agent to the posterior segment of the eye.
- the implant can also be located at a lower portion within the lens capsule.
- the implant can be oriented within the inferior periphery, annular periphery encircling the intraocular lens for at least 180 degrees, or the like as long as a line of sight is not obstructed.
- the molecular weight and molecular size of the active agent can affect delivery of the active agent to the posterior segment of the eye.
- the active agent can have a molecular weight of 250,000 daltons (Da) or less.
- the active agent can have a molecular weight of 170,000 Da or less.
- the active agent can have a molecular weight of 500 Da or less.
- active agents are known for the treatment or prophylaxis of various eye conditions, such as AMD (neovascular form or atrophic form), glaucoma, diabetic retinopathy, Retinopathy of Prematurity, uveitis, corneal transplant rejection, capsular fibrosis, posterior capsule opacification, retinal vein occlusions, infections, and the like.
- Any suitable active agent for incorporation into a biodegradable active agent matrix can be used, such as steroids, NSAIDs, antibiotics, anti-VEGF agents, PDGF-B inhibitors (Fovista®), integrin antagonists, complement antagonists, the like, or combinations thereof.
- Non-limiting examples of suitable active agents can include dexamethasone, prednisolone, bevacizumab (Avastin®), ranibizumab (Lucentis®), sunitinib, pegaptanib (Macugen®), moxifloxacin, gatifloxicin, besifloxacin, timolol, latanoprost, brimonidine, nepafenac, bromfenac, diclofenac, ketorolac, triamcinolone, difluprednate, fluocinolide, aflibercept, the like, or combinations thereof.
- Treatment regimens can additionally include various photodynamic therapies, and the like.
- the active agent can include dexamethasone.
- the bioerodible polymer matrix can include one or several excipients, which can depend on the duration of active agent delivery.
- active agent matrix materials can include polymeric and non-polymeric materials.
- suitable matrix materials include biodegradable polymers such as PLGA (different ratios of lactic to glycolide content and end groups such as acid or ester termination), PVA, PEG, PLA, PGA, hydroxypropylcellulose, sodium
- the active agent matrix can be a PLGA having about 45-80% PLA and 55-20% PGA such as about 65% PLA and 35% PGA, and in one case about 50% PLA and 50% PGA.
- the biodegradable active agent matrix comprises a low melt fatty acid such as, but not limited to, lauric acid, myrisitic acid, palmitic acid, stearic acid, arachidic acid, capric acid, oleic acid, palmitoleic acid, and mixtures thereof.
- the biodegradable active agent matrix can comprise a pharmaceutically acceptable disintegrant.
- the distintegrant can be a superdistintegrant.
- suitable disintigrants include crosslinked celluloses (e.g.
- croscarmellose Ac-Di- Sol, NYMCE ZSX, PRIMELLOSE, SOLUTAB, VIVASOL
- micro crystalline cellulose alginates
- crosslinked PVP e.g. CROSSPOVIDONE, KOLLIDON, POLYPLASDONE
- crosslinked starch soy polysaccharides, calcium silicate, salts thereof, and the like.
- the delivery device herein can be targeted for a relatively short delivery duration, such as less than eight weeks.
- the active agent has a delivery duration of from about two weeks to about six weeks. Delivery duration can be a function of the type of polymer used in the matrix, copolymer ratios, and other factors.
- biodegradable polymers can include at least one of poly(lactic-co-glycolide), hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyglycolide-polyvinyl alcohol, croscarmellose, polycaprolactone, eudragit LI 00, eudragit RSI 00, poly(ethylene glycol) 4000, poly(ethylene glycol) 8000 and poly(ethylene glycol) 20,000.
- the biodegradable active agent matrix can comprise poly(lactic-co-glycolide) having a copolymer ratio from 10/90 to 90/10 and in another case from 52/48 to 90/10.
- the copolymer ratio can be about 50/50. In another specific example, the copolymer ratio can be 52-78/48-22 and in another specific example from 60-90/40-10. Although degradation rates can be dependent on such proportions, additional alternative approaches can also be useful such as device coatings, particle encapsulation, and the like.
- Homogeneous delivery devices can be formed, for example, by mixing a polymer material with a loading amount of active agent to form a matrix dispersion.
- the loading amount can be chosen to correspond to the desired dosage during diffusion. Loading amount can take into account diffusion characteristics of the polymer and active agent, residual active agent, delivery time, and the like.
- the matrix dispersion can then be formed into the device shape using any suitable technique. For example, the matrix dispersion can be cast, sprayed and dried, extruded, stamped, or the like. Such configurations will most often be formed using a biodegradable matrix, although non-biodegradable materials can also be used.
- the device can be formed in situ from a suspension of the active agent within a biodegradable polymer matrix precursor. Upon delivery into the target site, the biodegradable polymer matrix precursor can form (via precipitation and/or polymerization) the biodegradable active agent matrix in situ.
- dexamethasone can be dispersed within a biodegradable active agent matrix.
- dexamethasone dosage amounts can vary, generally from about 100 meg to about 400 meg can be effective for these indications. More specifically, some patients may be categorized as low risk while others can be categorized as high risk due to various factors such as age, secondary complications, pre-existing conditions, etc. Most often, a low risk patient can benefit from a low dosage of about 100 meg to about 150 meg. In contrast, a high risk individual can be administered a high dosage of about 250 meg to about 350 meg.
- biodegradable implants can specifically designed and tested for the treatment of postoperative surgery inflammation and can deliver pharmaceutical active agent up to or about 2 weeks or more. Yet other biodegradable implants can be designed and tested for the treatment of postoperative surgery inflammation and uveitis and can deliver active agent up to or about 6- 8 weeks or more. Further, depending on the severity of the inflammation, one, two, more implants can be implanted per eye during surgery.
- the active agent delivery devices can optionally include additional active agents or other desired therapeutically beneficial substances.
- the device can include at least one secondary active agent.
- the active agent matrix can be homogenous or non- homogenous.
- the active agent delivery device can include a plurality of active agents and can be homogenous.
- the active agent delivery device can include a plurality of active agents and can be non-homogenous.
- one active agent can be coated on the surface of the implant.
- the implant can be formulated to have pre-designated regions or layers including different active agents.
- the implant can be formulated to have pre-designated regions or layers having the same active agent, but at different concentrations.
- an outer region or layer of the implant can have a higher concentration of the active agent to deliver a higher initial dose or burst of the active agent followed by a prolonged lower dose over a period of days or weeks.
- different regions of the implant can be adapted to biodegrade at different rates.
- agents can optionally be coated on the implant to reduce the incidence of capsular fibrosis. Non-limiting examples of such agents include anti-cell proliferative agents, anti-TGF -beta agents, a5bl integrin antagonists, rapamycin, and the like.
- the ocular active agent delivery device can be configured to fit within a lens capsule or ciliary sulcus of an eye.
- the delivery device can be shaped in any geometry which allows for insertion into the lens capsule or ciliary sulcus.
- the implant can be in the shape of round, square shape, crescent, or donut shape.
- other suitable shapes can include, but are not limited to, discs, pellets, rods, and the like.
- dimensions can vary, typical dimensions can range from about 0.5 mm to about 4 mm width and about 0.2 mm to about 1 mm thickness.
- the total mass of the delivery device can vary, most often the total mass can be from 0.2 mg to 4 mg, or from about 1.5 mg to about 2.5 mg. For example, about 2 mg total mass can provide effective active agent volume, while also balancing overall size to fit within the target tissue areas.
- the implant can be shaped as a disc or pellet.
- the implant can typically have a diameter ranging from about 0.4 millimeters (mm) to about 3 mm, from about 0.5 mm to about 1.5 mm, or from about 0.7 mm to about 1.3 mm.
- the disc- or pellet-shaped implant can typically have a thickness ranging from about 0.2 mm to about 2 mm, from about 0.8 mm to about 1.5 mm, or from about 0.3 mm to about 1.0 mm.
- FIG. 1 One example of a pellet or disc is illustrated in FIG. 1 , which has a diameter of about 2 to 2.5 mm and a thickness of about 1.0-1.5 mm.
- the implant can have rounded edges, hemispherical, or semi-circular shapes.
- the implant can be shaped as a rod.
- the implant can typically have a diameter ranging from about 0.05 mm to about 2 mm, from about 0.1 mm to about 1.0 mm, or from about 0.2 mm to about 0.8 mm.
- the rod-shaped implant can typically have a length ranging from about 0.5 mm to about 5 mm, from about 1.0 mm to about 3.0 mm, or from about 1.5 mm to about 2.5 mm.
- Yet another aspect of the present invention provides a method of delivering an active agent into an eye of a subject. It is noted that when discussing various examples and embodiments of the implantable devices, systems, and methods described herein, each of these respective discussions can also apply to each of the other aspects of the present invention. Thus, for example, when discussing the implantable device per se, this discussion is also relevant to the methods discussed herein, and vice versa.
- the method can include placing a biodegradable active agent matrix, as described herein, within a lens capsule of a subject to deliver the active agent to a posterior segment of the eye.
- the biodegradable active agent matrix can include an active agent in an amount to deliver a therapeutically effective dose of the active agent to the posterior segment of the eye from the lens capsule.
- the method can include performing a cataract removal surgery on the eye of the subject, further including removing an existing lens from the eye of the subject, inserting an intraocular lens into the eye of the subject, and placing the biodegradable active agent matrix within the lens capsule.
- the biodegradable active agent matrix or implant can be associated with the intraocular lens.
- the delivery device may be attached or detached from an intraocular lens.
- the delivery device can be associated by actual contact or sufficient proximity while allowing effective diffusion of active agent to target areas of the eye.
- a biodegradable system can have substantial value in routine cataract surgery to provide short-term/time-limited delivery of postoperative medicines while minimizing or eliminating the need for eyedrop usage by the patient.
- the lens that is removed can be the original natural lens of the eye, or it can be a lens that was previously inserted into the eye as a result of a prior procedure.
- the implant can be associated with the intraocular lens prior to inserting the intraocular lens into the eye.
- it can be necessary to configure the implant to comply with any requirements of the surgical procedure.
- cataract surgeries are often performed through a small incision.
- One standard size incision is about 2.75 mm; although this device can be compatible with smaller or larger incision sizes as well.
- the intraocular lens assembly can be shaped to allow insertion through this small opening.
- the active agent delivery device can also be configured to be inserted with the intraocular lens assembly, e.g. by shape and/or choice of resilient and flexible material for the implant.
- the active agent delivery device can also be physically coupled or decoupled to the intraocular lens assembly prior to insertion of the assembly into the eye.
- the implant can be positioned within the lens capsule, and optionally associated with the intraocular lens assembly, following insertion of the lens into the eye.
- the capsular bag can be readily reopened for a patient having prior cataract surgery.
- the insertion of the delivery device can be performed immediately prior to insertion of an intraocular lens or later in time as a separate procedure.
- a standard clear-corneal phacoemulsification with intraocular lens (Acrysof SA60AT; Alcon) implantation was performed on 35 rabbits.
- an intraocular device containing an active agent was inserted into a lens capsule of each rabbit.
- the rabbits were divided into 4 groups, depending on the active agent in the intraocular device.
- Devices were loaded with 5-15 mg of either Avastin, Timolol, Brimonidine, or Latanoprost.
- Each group was evaluated to determine the intraocular device and lens stability, capsular fibrosis, and healing of cataract wounds and anterior segment.
- a subgroup of eyes was evaluated weekly for 4 weeks for inflammation and harvested at 1 month for histopathologic evaluation of capsular and CDR integrity.
- Example 2 The surgery and setup as described in Example 1 was repeated, with the exception that aqueous and vitreous taps were performed biweekly and assayed for drug concentrations with HPLC and/or ELISA.
- half of the eyes were harvested at one month and the other half at two months. This was accomplished as follows : immediately after sacrificing the rabbit and enucleating the eye, the eye was frozen in liquid nitrogen to prevent perturbation and redistribution of drug in eye tissues. The eye was then dissected into 3 parts (aqueous humor, vitreous and retina/choroid layer) to evaluate anatomic toxicity and tissue drug concentration.
- the intraocular device was retrieved and assessed for remaining drug amounts.
- the distribution profile of the intraocular device was compared with the conventional intravitreal injection of 2.5 mg/0.1 cc Avastin® for direct comparison of the different delivery methods.
- eyes from the remaining subgroups of rabbits were enucleated, fixed by 10% formalin, embedded in paraffin, step sectioned, stained by hematoxyline and eosin (H & E), and examined for histological changes.
- FIG. 5 shows the amount of Avastin assayed per ocular region at 1 week post implantation.
- microparticles were prepared using PLGA [poly(d,l-lactide-co-glycolide), MW. 7000-17000, acid terminated], hydroxypropyl methyl cellulose (HPMC) and dexamethasone.
- PLGA poly(d,l-lactide-co-glycolide), MW. 7000-17000, acid terminated] hydroxypropyl methyl cellulose (HPMC) and dexamethasone.
- Dexamethasone loaded PLGA microspheres were prepared using standard oil-in-water (o/w) emulsion-solvent extraction method. An amount of 160 mg PLGA was dissolved in 4 mL methylene chloride and 1 mL acetonitrile.
- microparticles were separated by centrifugation, washed twice, resuspended in deionized water, and freeze-dried to obtain lyophilized particles.
- the prepared microparticles were characterized and pelleted using bench top pellet press with 2 mm die set to form an implant.
- dexamethasone flow was bidirectional from the endocapsular space into both the anterior and posterior chambers. There were also no cells or formation of fibrin in the anterior and posterior chambers of the eye. Histological examinations revealed all the tissues examined were normal and showed no signs of inflammation.
- All the study animals were acquainted to study room conditions once they are out of quarantine and randomized. All the positive control group and implantation groups underwent phacoemulsification and insertion of an intraocular lens (IOL) in both the eyes. Group III and IV received one and two implants per eye respectively.
- IOL intraocular lens
- Intraocular pressure was normal in all the groups. Further, there were no signs of anterior or posterior chamber inflammation as assessed with Slit lamp biomicroscopy and confirmed by histological examination. There was a trend in increase in retinal thickness in animals treated with dexamethasone drops whereas, implants maintained retinal thickness.
- the PLGA polymer degrades in to lactic and glycolic acid through hydrolysis, then further degrades in to carbon dioxide and water before eliminating from the body. Implants did not migrate to the center to obstruct the visual field.
- BDI-1 implant was manufactured by following partial solvent casting method with subsequent evaporation and removing the residual solvent by drying the product under high vacuum for 3 days.
- Various implants were prepared using PLGA [poly(d,l-lactide-co- glycolide), MW. 7000-17000, acid terminated], hydroxypropyl methyl cellulose (HPMC), croscarmellose sodium (cross linked sodium carboxymethylcellulose), hydroxypropyl cellulose and dexamethasone in several different compositions.
- the dried particles were directly pelleted using bench top pellet press with a 2 mm die set to form an implant.
- the selected BDI-1 implants (from in-vitro release studies, FIG. 7) were sterilized, implanted in the capsular bag of rabbit's eyes. Two implants with different composition and dose were tested in-vivo in NZW rabbits to establish pharmacokinetics. Two rabbits were sacrificed at 2, 6, 10, 15 days and various tissue samples (aqueous humor, vitreous humor, IOL, iris/ciliary body and retina/choroid) were collected and samples were analyzed by a validated LC/MS/MS method. Pharmacokinetics with near zero order kinetics was observed in rabbits up to 15 days. Further, dexamethasone flow was bidirectional from the
- endocapsular space into both the anterior and posterior chambers. There were also no cells or formation of fibrin in the anterior and posterior chambers of the eye. Histological examinations revealed all the tissues examined were normal and showed no signs of inflammation.
- DXM concentrations are presented in FIG. 8 FIG. 9.
- the implants eroded slowly over 10 days and reaching trough concentrations of DXM by day 15.
- the implants are degraded by 80% of its mass by day 15 and expected to fully degrade by day 20.
- Therapeutic concentrations of DXM was found up to day 15 with minimal systemic exposure ( ⁇ 23 ng/mL), whereas, with dexamethasone drops systemic exposure was higher (>150 ng/mL during week 1 , in-house data).
- biodegradable implants were prepared with PLGA, croscarmellose sodium, and dexamethasone in accordance with Table 3 below.
- Drug release profiles for each of the listed formulations were obtained using an in- vitro drug release model. Individual drug release profiles are presented in FIG. 10. As illustrated in FIG. 10, increasing amounts of croscarmellose can increase the drug release rate from the biodegradable implant as compared to a biodegradable implant prepared with only PLGA.
- Two biodegradable dexamethasone implants were prepared using different formulations including PLGA, croscarmellose, and dexamethasone.
- the first BDI was configured to deliver 200 meg dexamethasone over a period of two weeks.
- the second BDI was configured to deliver 300 meg dexamethasone over a period of six weeks.
- the drug release profiles were evaluating using an in- vitro drug release model. The release profile for the first and second BDIs are illustrated in FIGs. 11 and 12, respectively.
- Dexamethasone concentration profiles for each of the ocular regions are presented in FIGs. 13 through FIG. 16. Further, the retinal thicknesses for each of the test subjects were measured over time and compared to retinal thicknesses for test subjects treated with a topical formulation and control subjects with normal retinal thickness. These results are depicted in FIG. 17. As illustrated in FIG. 17, a therapeutically effective dose can reduce retinal thickening associated with an ocular condition as compared to retinal thickening without treatment or as compared to treatment with a topical formulation.
- Dexamethasone concentration profiles for each of the ocular regions are presented in FIGs. 18 through FIG. 21. Further, the retinal thicknesses for each of the test subjects were measured over time and compared to retinal thicknesses for test subjects treated with a topical formulation and control subjects with normal retinal thickness. These results are depicted in FIG. 22. As illustrated in FIG. 22, a therapeutically effective dose can reduce retinal thickening associated with an ocular condition as compared to retinal thickening without treatment or as compared to treatment with a topical formulation.
Abstract
Description
Claims
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US11185441B2 (en) | 2019-06-27 | 2021-11-30 | Layerbio, Inc. | Ocular device delivery methods and systems |
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WO2020023290A1 (en) | 2018-07-23 | 2020-01-30 | The Regents Of The University Of Colorado, A Body Corporate | Ophthalmic device for drug delivery |
KR102191180B1 (en) * | 2019-05-31 | 2020-12-15 | 삼진제약주식회사 | A composition for treating eye diseases |
US11399977B2 (en) | 2020-06-04 | 2022-08-02 | SpyGlass Pharma, Inc. | Ophthalmic implant system for drug delivery |
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AU1447095A (en) * | 1993-12-30 | 1995-07-17 | Arcturus Pharmaceutical Corporation | Methods for the treatment of the central nervous system or eye involving pathogenic oxidation pathways |
US20050244469A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Extended therapeutic effect ocular implant treatments |
US7931909B2 (en) * | 2005-05-10 | 2011-04-26 | Allergan, Inc. | Ocular therapy using alpha-2 adrenergic receptor compounds having enhanced anterior clearance rates |
EP1998718A1 (en) * | 2006-03-30 | 2008-12-10 | Universite De Geneve | Intraocular lens with drug delivery system attached thereto |
JP2010536797A (en) * | 2007-08-16 | 2010-12-02 | マクサイト, インコーポレイテッド | Formulations for treating eye diseases or conditions |
JP5222550B2 (en) * | 2007-12-27 | 2013-06-26 | 財團法人工業技術研究院 | Sustained release composition and method for producing the same |
WO2009140246A2 (en) * | 2008-05-12 | 2009-11-19 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US10064819B2 (en) * | 2008-05-12 | 2018-09-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
WO2010059214A2 (en) * | 2008-11-20 | 2010-05-27 | Insight Innovations, Llc | Biocompatible biodegradable intraocular implant system |
JP6543431B2 (en) * | 2013-10-10 | 2019-07-10 | ユニバーシティー オブ ユタ リサーチ ファウンデーションUniversity of Utah Research Foundation | Intraocular drug delivery device and associated method |
CA2830555A1 (en) * | 2013-10-18 | 2015-04-18 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
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